tbuckley/cabot-search huggingface dataset:
The genetic background shapes the susceptibility to mitochondrial dysfunction and NASH progression
Authors: Giorgia Benegiamo, Giacomo V.G. von Alvensleben, Sandra Rodríguez-López, Ludger J.E. Goeminne, Alexis M. Bachmann, Jean-David Morel, Ellen Broeckx, Jing Ying Ma, Vinicius Carreira, Sameh A. Youssef, Nabil Azhar, Dermot F. Reilly, Katharine D’Aquino, Shannon Mullican, Maroun Bou-Sleiman, Johan Auwerx
Journal: The Journal of Experimental Medicine (2023)

Non-alcoholic steatohepatitis (NASH) is a global health concern without treatment. The challenge in finding effective therapies is due to the lack of good mouse models and the complexity of the disease, characterized by gene–environment interactions. We tested the susceptibility of seven mouse strains to develop NASH. The severity of the clinical phenotypes observed varied widely across strains. PWK/PhJ mice were the most prone to develop hepatic inflammation and the only strain to progress to NASH with extensive fibrosis, while CAST/EiJ mice were completely resistant. Levels of mitochondrial transcripts and proteins as well as mitochondrial function were robustly reduced specifically in the liver of PWK/PhJ mice, suggesting a central role of mitochondrial dysfunction in NASH progression. Importantly, the NASH gene expression profile of PWK/PhJ mice had the highest overlap with the human NASH signature. Our study exposes the limitations of using a single mouse genetic background in metabolic studies and describes a novel NASH mouse model with features of the human NASH.
Delaying the Onset of Nearsightedness
Authors: David A. Berntsen, Jeffrey J. Walline
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Waking immune-resistant tumors with neddylation
Authors: Kristin Huntoon, Wen Jiang, Betty Y.S. Kim
Journal: Journal of Clinical Investigation (2023)

The CD47/signal regulatory protein α (SIRPα) axis, which functions as an inhibitory phagocytosis checkpoint, also serves as a key mediator in cancer immune evasion. Many cancers, including colorectal cancer (CRC), exploit the expression of CD47 to escape phagocytic clearance and activate the innate immune system. Previous work has indicated that distinct paradigms of posttranslational modifications mediate the regulatory mechanisms of the CD47/SIRPα axis. In this issue of the JCI, Li et al. show that neddylation, a ubiquitin-like modification, inactivates Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), a downstream target of this pathway. They further show that inhibition of SHP2 sensitizes CRC cells to immunotherapies to which they were previously resistant. Collectively, the results underscore the need for cotargeting SHP2 and immune checkpoints (e.g., programmed death 1 [PD1]) in CRC and possibly other immunotherapy-resistant tumors.
Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project
Authors: Jason M. Devgun, Rongmei Zhang, Jeffrey Brent, Paul Wax, Keith Burkhart, Alison Meyn, Sharan Campleman, Stephanie Abston, Kim Aldy, Maryann Amirshahi, Katherine Boyle, Jennie Buchanan, Jennifer Carey, Kennon Heard, Robert Hendrickson, Ziad Kazzi, Eric Lavonas, Michael Levine, Travis Olives, Anthony Pizon, Jonathan Schimmel, Kapil Sharma, Meghan Spyres, Timothy Wiegand
Journal: JAMA Network Open (2023)

The rapid spread and mortality associated with COVID-19 emphasized a need for surveillance system development to identify adverse events (AEs) to emerging therapeutics. Bradycardia is a remdesivir infusion-associated AE listed in the US Food and Drug Administration-approved prescribing information.To evaluate the magnitude and duration of bradycardic events following remdesivir administration.A multicenter cohort study of patients with recorded heart rate less than 60 beats per minute within 24 hours after administration of a remdesivir dose was conducted between November 23, 2020, and October 31, 2021. Participants included patients hospitalized with COVID-19 at 15 medical centers across the US. Patients excluded had AEs unrelated to bradycardia, AEs in addition to bradycardia, or first onset of bradycardia after 5 remdesivir doses.Remdesivir administration.Linear mixed-effect models for the minimum HR before starting remdesivir and within 24 hours of each dose included doses as fixed effects. Baseline covariates were age (≥65 years vs <65 years), sex (male vs female), cardiovascular disease history (yes vs no), and concomitant use of bradycardia-associated medications. The interactions between variables and doses were considered fixed-effects covariates to adjust models.A total of 188 patients were included in the primary analysis and 181 in the secondary analysis. The cohort included 108 men (57.4%); 75 individuals (39.9%) were non-Hispanic White and mean (SD) age was 61.3 (15.4) years. Minimum HR after doses 1 to 5 was lower than before remdesivir. Mean minimum HR was lowest after dose 4, decreasing by -15.2 beats per minute (95% CI, -17.4 to -13.1; P < .001) compared with before remdesivir administration. Mean (SD) minimum HR was 55.6 (10.2) beats per minute across all 5 doses. Of 181 patients included in time-to-event analysis, 91 had their first episode of bradycardia within 23.4 hours (95% CI, 20.1-31.5 hours) and 91 had their lowest HR within 60.7 hours (95% CI, 54.0-68.3 hours). Median time to first bradycardia after starting remdesivir was shorter for patients aged 65 years or older vs those younger than 65 years (18.7 hours; 95% CI, 16.8-23.7 hours vs 31.5 hours; 95% CI, 22.7-39.3 hours; P = .04). Median time to lowest HR was shorter for men vs women (54.2 hours; 95% CI, 47.3-62.0 hours vs 71.0 hours; 95% CI, 59.5-79.6 hours; P = .02).In this cohort study, bradycardia occurred during remdesivir infusion and persisted. Given the widespread use of remdesivir, practitioners should be aware of this safety signal.
Reaffirmed USPSTF Recommendation Against Serologic Screening for Genital Herpes
Authors: Howa Yeung, Anandi N. Sheth, Lauren F. Collins
Journal: JAMA Dermatology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Interleukin‐23 Regulates Inflammatory Osteoclastogenesis via Activation of <i>CLEC5A</i>(+) Osteoclast Precursors
Authors: Hiroki Furuya, Cuong Thach Nguyen, Ran Gu, Shie‐Liang Hsieh, Emanual Maverakis, Iannis E. Adamopoulos
Journal: Arthritis & Rheumatology (2023)

To investigate the role of interleukin-23 (IL-23) in pathologic bone remodeling in inflammatory arthritis.
Mitochondrial function in macrophages controls cardiac repair after myocardial infarction
Authors: David Weissman, Christoph Maack
Journal: Journal of Clinical Investigation (2023)

Cardiac healing following acute myocardial infarction (MI) involves the mobilization and activation of immune cells, including macrophages. In the early phase after MI, macrophages adopt a proinflammatory phenotype, while polarizing toward a reparative one in the late stage. Although metabolic reprogramming has been observed during this transition, the mechanistic links to macrophage differentiation are still poorly understood. In this issue of the JCI, Cai, Zhao and colleagues demonstrate that mitochondrial function in macrophages governed the resolution of inflammation and tissue repair by modulating the phagocytic removal of apoptotic cells (so-called efferocytosis) as well as myofibroblast activation. These findings provide important mechanistic insights into the potential relevance of metabolic modulation of macrophage functions following MI, which might lead to alternative therapeutic strategies for MI.
Molecular mechanisms of amyotrophic lateral sclerosis as broad therapeutic targets for gene therapy applications utilizing adeno‐associated viral vectors
Authors: Jessica Merjane, Roger Chung, Rickie Patani, Leszek Lisowski
Journal: Medicinal Research Reviews (2023)

Despite the devastating clinical outcome of the neurodegenerative disease, amyotrophic lateral sclerosis (ALS), its etiology remains mysterious. Approximately 90% of ALS is characterized as sporadic, signifying that the patient has no family history of the disease. The development of an impactful disease modifying therapy across the ALS spectrum has remained out of grasp, largely due to the poorly understood mechanisms of disease onset and progression. Currently, ALS is invariably fatal and rapidly progressive. It is hypothesized that multiple factors can lead to the development of ALS, however, treatments are often focused on targeting specific familial forms of the disease (10% of total cases). There is a strong need to develop disease modifying treatments for ALS that can be effective across the full ALS spectrum of familial and sporadic cases. Although the onset of disease varies significantly between patients, there are general disease mechanisms and progressions that can be seen broadly across ALS patients. Therefore, this review explores the targeting of these widespread disease mechanisms as possible areas for therapeutic intervention to treat ALS broadly. In particular, this review will focus on targeting mechanisms of defective protein homeostasis and RNA processing, which are both increasingly recognized as design principles of ALS pathogenesis. Additionally, this review will explore the benefits of gene therapy as an approach to treating ALS, specifically focusing on the use of adeno-associated virus (AAV) as a vector for gene delivery to the CNS and recent advances in the field.
The gut signals to AGRP-expressing cells of the pituitary to control glucose homeostasis
Authors: Shun-Mei Liu, Bruno Ifebi, Fred Johnson, Alison Xu, Jacquelin Ho, Yunlei Yang, Gary Schwartz, Young Hwan Jo, Streamson Chua
Journal: Journal of Clinical Investigation (2023)

Glucose homeostasis can be improved after bariatric surgery that alters bile flow and stimulate gut hormone secretion, in particular FGF15/19. FGFR1 expression in AGRP expressing cells is required for bile acids's ability to improve glucose control. We show that the mouse Agrp gene has 3 promoter/enhancer regions that direct transcription of each of their own AGRP transcripts. One of these Agrp promoters/enhancers, Agrp B, is regulated by bile acids. We generated an Agrp B knock-in FLP/knockout allele. AGRP B expressing cells are found in endocrine cells the pars tuberalis (PT) and co-expressDAGLB (an endocannabinoid biosynthetic enzyme), distinct from PT thyrotropes. AGRP B expression is also found in the folliculostellate cells of the pituitary's anterior lobe. Mice without AGRP B are protected from high fat feeding induced glucose intolerance but not excess weight gain. Chemogenetic inhibition of AGRP B cells improves glucose tolerance by enhancing glucose stimulated insulin secretion. Inhibition of the AGRP B cells also caused weight loss. The improved glucose tolerance and reduced body weight persisted up to 6 weeks after cessation of the DREADD mediated inhibition, suggesting the presence of a biological switch for glucose homeostasis that is regulated by long term stability of food availability.
A <scp>24‐Week</scp> , Phase <scp>IIa</scp> , Randomized, Double‐blind, Placebo‐controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis ( <scp>NOVESA</scp> )
Authors: Dinesh Khanna, Christopher P. Denton, Daniel E. Furst, Maureen D. Mayes, Marco Matucci‐Cerinic, Vanessa Smith, Dick de Vries, Paul Ford, Yasmina Bauer, Matthew J. Randall, Mitra Ebrahimpoor, Laszlo Kupcsik, Pieter‐Jan Stiers, Liesbeth Deberdt, Niyati Prasad, Sharlene Lim, Philippe Pujuguet, Sohail Ahmed
Journal: Arthritis & Rheumatology (2023)

Objective We undertook this study to explore the efficacy, safety, and tolerability of ziritaxestat, a selective autotaxin inhibitor, in patients with early diffuse cutaneous systemic sclerosis (dcSSc). Methods NOVESA was a 24‐week, multicenter, phase IIa, double‐blind, placebo‐controlled study. Adults with dcSSc were randomized to oral ziritaxestat 600 mg once daily or matching placebo. The primary efficacy end point was change from baseline in modified Rodnan skin score (MRSS) at week 24. Secondary end points assessed safety and tolerability; other end points included assessment of skin and blood biomarkers. Patients in NOVESA could enter a 104‐week open‐label extension (OLE). Results Patients were randomized to ziritaxestat (n = 21) or placebo (n = 12). Reduction in MRSS was significantly greater in the ziritaxestat group versus the placebo group (–8.9 versus –6.0 units, respectively; P = 0.0411). Placebo patients switching to ziritaxestat in the OLE showed similar reductions in MRSS to those observed for ziritaxestat patients in the parent study. Ziritaxestat was well tolerated; the most frequent treatment‐related treatment‐emergent adverse events were headache and diarrhea. Circulating lysophosphatidic acid (LPA) C18:2 was significantly reduced, demonstrating ziritaxestat target engagement, and levels of fibrosis biomarkers were reduced in the blood. No differentially expressed genes were identified in skin biopsies. Significant changes in 109 genes were identified in blood samples. Conclusion Ziritaxestat resulted in significantly greater reduction in MRSS at week 24 than placebo; no new safety signals emerged. Biomarker analysis suggests ziritaxestat may reduce fibrosis. Modulation of the autotaxin/LPA pathway could improve skin involvement in patients with dcSSc. A plain language summary is provided in the Supplementary Material, available on the Arthritis &amp; Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42477 . image
Chronic myelomonocytic leukemia transdifferentiation landscape: From histiocytosis to blastic plasmacytoid dendritic cell neoplasm
Authors: Gabriel Antherieu, Marie Donzel, Brigitte Balme, Alexandra Traverse‐Glehen, Maël Heiblig
Journal: American Journal of Hematology (2023)

A 70-year-old man presented with splenomegaly, weight loss, and cytopenias. Marrow assessment led to the diagnosis of chronic myelomonocytic leukemia (CMML) (Image 1A, next-generation sequencing Illumina was performed on non-sorted/bulk cell population from bone marrow), mainly myelodysplastic form (leukocytosis <13G/L), and flow cytometry (FCM) found 0.2%–0.3% of physiological plasmacytoid dendritic cells. Cutaneous and nasal infiltrative lesions were associated (Image 1, panel H), which were revealed to be composed of atypical histiocytic cells (Image 1, panel B) expressing PS100 and CD68 (Image 1, panel C/D), leading to the diagnosis of histiocytosis of the L group (Associated with another myeloproliferative/myelodysplastic disorder); lysozyme staining was positive in a few cells; CD56 and BDCA2 staining were both negative. There was no argument for myeloid sarcoma. Ruxolitinib (JAK inhibitor) combined to cobimetinib (MEK inhibitor) was initiated and led to partial metabolic response and cytopenias improvement after 1 month (Image 1, panel I, PET). The patient progressed for 3 months thereafter with recurring skin lesions. Ruxolitinib was switched to azacitidine in association with cobimetinib. After 2 cycles, patient reached complete metabolic response (Image 1, panel J). One year later, he relapsed with various skin lesions. Biopsied revealed a dense dermal infiltration by medium- to large-sized cells with irregular nucleus (Image 1, panel E) expressing CD56/BDCA2, but not PS100/CD68/Lysozyme (Image 1, panel F/G), leading to the diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) with clonal evolution (Image 1, panel A). Blood FCM found 0.1% of circulating abnormal BPDCN cells, marrow examination was not done. This case not only illustrates the plasticity between CMML, BPDCN,1 and histiocytosis2, 3 but also potential therapeutic value of MEK inhibitors in combination with azacitidine in RAS-mutated CMML, especially in case of extra-medullar involvement.4 The authors declare no conflicts of interest. Data available on request due to privacy/ethical restrictions
Guanylyl cyclase C ameliorates visceral pain: an unsuspected link
Authors: Rodger A. Liddle
Journal: Journal of Clinical Investigation (2023)

Visceral pain associated with irritable bowel syndrome afflicts 15% of the US population. Although treatments are limited, guanylyl cyclase C (GUCY2C) agonists alleviate pain and constipation. Until now, it was assumed that the activation of GUCY2C and production of cGMP in enterocytes stimulated fluid secretion and reduced visceral sensation. The recent discovery that a subtype of enteroendocrine cells (EECs) known as neuropod cells synapse with submucosal neurons unveiled a pathway for communicating gut signals to the nervous system. In this issue of the JCI, Barton et al. report that GUCY2C is enriched in neuropod cells and is involved with sensory nerve firing. Selective deletion of GUCY2C in mouse models suggests that defective GUCY2C neuropod–cell signaling underlies visceral pain. These studies introduce possibilities for dissociating the secretory and analgesic effects of GUCY2C agonism. Although further work remains, unveiling the role of neuropod cells is a major step in understanding visceral pain.
NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22
Authors: Marianne R. Spalinger, Stephanie Kasper, Claudia Gottier, Silvia Lang, Kirstin Atrott, Stephan R. Vavricka, Sylvie Scharl, Petrus M. Gutte, Markus G. Grütter, Hans-Dietmar Beer, Emmanuel Contassot, Andrew C. Chan, Xuezhi Dai, David J. Rawlings, Florian Mair, Burkhard Becher, Werner Falk, Michael Fried, Gerhard Rogler, Michael Scharl
Journal: Journal of Clinical Investigation (2023)

The authors recently became aware of errors in Figure 8, A and B. In Figure 8A, the WT/H 2 O and WT/DSS pictures were inadvertently switched.In Figure 8B, the incorrect image was shown for the Ptpn22 -/-/DSS sample.The correct figure is shown below.
SARS-CoV-2 Infections and Presymptomatic Type 1 Diabetes Autoimmunity in Children and Adolescents—Reply
Authors: Marian Rewers, Anette-Gabriele Ziegler
Journal: JAMA (2023)

In Reply We welcome the opportunity to address the comments expressed by Dr Chang about our recent Research Letter,1 which found no association between SARS-CoV-2 infection and presymptomatic type 1 diabetes.
Tumor-specific activated nano-domino-CRISPR to amplify intrinsic oxidative and activate endogenous apoptosis for spatiotemporally specific therapy
Authors: Li Wang, Chao Liu, Xinxin Wang, Shuang Ma, Furong Liu, Yi Zhang, Yan Wang, Meiling Shen, Xinyue Wu, Qinjie Wu, Changyang Gong
Journal: Biomaterials (2023)
Prediction of Response to Lenvatinib Monotherapy for Unresectable Hepatocellular Carcinoma by Machine Learning Radiomics: A Multicenter Cohort Study
Authors: Zhiyuan Bo, Bo Chen, Zhengxiao Zhao, Qikuan He, Yicheng Mao, Yunjun Yang, Fei Yao, Yi Yang, Ziyan Chen, Jinhuan Yang, Haitao Yu, Jun Ma, Lijun Wu, Kaiyu Chen, Luhui Wang, Mingxun Wang, Zhehao Shi, Xinfei Yao, Yulong Dong, Xintong Shi, Yunfeng Shan, Zhengping Yu, Yi Wang, Gang Chen
Journal: Clinical Cancer Research (2023)

Abstract Purpose: We aimed to construct machine learning (ML) radiomics models to predict response to lenvatinib monotherapy for unresectable hepatocellular carcinoma (HCC). Experimental Design: Patients with HCC receiving lenvatinib monotherapy at three institutions were retrospectively identified and assigned to training and external validation cohorts. Tumor response after initiation of lenvatinib was evaluated. Radiomics features were extracted from contrast-enhanced CT images. The K-means clustering algorithm was used to distinguish radiomics-based subtypes. Ten ML radiomics models were constructed and internally validated by 10-fold cross-validation. These models were subsequently verified in an external validation cohort. Results: A total of 109 patients were identified for analysis, namely, 74 in the training cohort and 35 in the external validation cohort. Thirty-two patients showed partial response, 33 showed stable disease, and 44 showed progressive disease. The overall response rate (ORR) was 29.4%, and the disease control rate was 59.6%. A total of 224 radiomics features were extracted, and 25 significant features were identified for further analysis. Two distant radiomics-based subtypes were identified by K-means clustering, and subtype 1 was associated with a higher ORR and longer progression-free survival (PFS). Among the 10 ML algorithms, AutoGluon displayed the highest predictive performance (AUC = 0.97), which was relatively stable in the validation cohort (AUC = 0.93). Kaplan–Meier analysis showed that responders had a better overall survival [HR = 0.21; 95% confidence interval (CI): 0.12–0.36; P &amp;lt; 0.001] and PFS (HR = 0.14; 95% CI: 0.09–0.22; P &amp;lt; 0.001) than nonresponders. Conclusions: Valuable ML radiomics models were constructed, with favorable performance in predicting the response to lenvatinib monotherapy for unresectable HCC.